Pancreatic cancer, the fourth leading cause of cancer mortality in the U.S., is resistant to all standard therapies (overall 5-year survival rate, 5%), highlighting the need for novel treatments. T cells have the capacity to actively infiltrate fibrotic tissue, and adoptively transferred, in v/Y/'o-expanded cytotoxic T lymphocytes (CTLs) targeting tumor-associated antigens can effectively traffic to distant tumor sites, infiltrate even bulky tumor masses and eradicate disseminated tumor cells in a range of malignancies, including Hodgkin lymphoma, nasopharyngeal carcinoma, neuroblastoma and melanoma. Whether this therapy can be successfully extended to the treatment of patients with pancreatic cancer will likely depend on the development of strategies to ensure tumor specificity and circumvention of the adverse effects of the tumor microenvironment, which limits the in vivo persistence and function of the transferred T cells. In this new Project 2 { A. Leen and W. Fisher) will generate cytotoxic T lymphocyte (CTL) lines that target mesothelin (MSLN), a glycoprotein overexpressed in 80-90% of pancreatic carcinomas and containing epitopes recognized by T cells. These cells will then be engineered to express a novel chimeric cytokine receptor (IL4/7R) that should allow them to resist the tumor microenvironment by inverting the function of the immunoinhibitory cytokine IL4 to transmit an immunostimulatory signal that will sustain the expansion and cytolytic function of the infused cells (Aim 1). This strategy, to be tested in a phase I clinical trial in patients with advanced pancreatic cancer (Aims 2 and 3) should safely ensure the sustained function of tumor-targeted T cells in vivo, even in the immunosuppressive tumor microenvironment, and enhance the potency of adoptively transferred T cells. Engineering mesothelin-specific T cells to express a chimeric cytokine receptor that binds the abundant Th2 cytokine IL4, while maintaining a Thi effector phenotype and cytotoxic function, represents a novel achievement in the field, one that may well advance treatment for this devastating tumor. Our project could potentially make use of the icaspQ safety gene developed by Project 1 and the CAR targeting CAF that Project 4 is developing and can provide additional means of enhancing anti-tumor activity to all projects in the program. RELEVANCE (See instructions): Few other solid tumors carry the dire prognosis of pancreatic cancer. To meet the urgent need for useful treatment of this malignancy, investigators in this project have engineered a chimeric cytokine receptor that will both stimulate the expansion and persistence of the modified tumor-directed T cells, as well as protect them from the adverse effects of the surrounding microenvironment.